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1.  Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes  
Journal of Clinical Investigation  2006;116(12):3171-3182.
Anaplastic large cell lymphomas (ALCLs) represent a subset of lymphomas in which the anaplastic lymphoma kinase (ALK) gene is frequently fused to the nucleophosmin (NPM) gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that ALK activity is strictly required for the survival of ALK-positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK-positive ALCL cell lines, abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell-permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBPβ and the antiapoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK-positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions.
doi:10.1172/JCI29401
PMCID: PMC1636692  PMID: 17111047
2.  NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma 
Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma of T/null immunophenotype that is most prevalent in children and young adults. The normal cellular counterpart of this malignancy is presumed to be the cytotoxic T lymphocyte (CTL), and this presumption is partly based on the observation that these tumour cells often express cytotoxic granules containing Granzyme B (GzB) and Perforin. Chromosomal translocations involving the gene encoding for the ALK tyrosine kinase are also characteristic of ALK+ ALCL, and the resulting fusion proteins (e.g. NPM-ALK) initiate signalling events important in ALK+ ALCL pathogenesis. These events include the elevated expression of JunB; an AP-1 family transcription factor that promotes ALK+ ALCL proliferation. In this report we demonstrate that JunB is a direct transcriptional activator of GzB and that GzB transcription is also promoted by NPM-ALK. We found that Perforin expression was not regulated by JunB, but was promoted by NPM-ALK in some cell lines and inhibited by it in others. In conclusion, our study makes the novel observation that signalling through NPM-ALK and JunB affect the expression of cytotoxic molecules in ALK+ ALCL. Moreover, these findings demonstrate the expression of GzB and Perforin in this lymphoma is not solely due its presumed CTL origin, but that oncogenic signalling is actively influencing the expression of these proteins.
PMCID: PMC3037198  PMID: 21326808
ALK+ ALCL; JunB; NPM-ALK; granzyme B; perforin
3.  Aberrant Anaplastic Lymphoma Kinase Activity Induces a p53 and Rb-Dependent Senescence-Like Arrest in the Absence of Detectable p53 Stabilization 
PLoS ONE  2011;6(3):e17854.
Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in a variety of tumor types, most notably in Anaplastic Large Cell Lymphoma (ALCL) where a chromosomal translocation generates the oncogenic fusion protein, Nucleophosmin-ALK (NPM-ALK). Whilst much is known regarding the mechanism of transformation by NPM-ALK, the existence of cellular defence pathways to prevent this pathological process has not been investigated. Employing the highly tractable primary murine embryonic fibroblast (MEF) system we show that cellular transformation is not an inevitable consequence of NPM-ALK activity but is combated by p53 and Rb. Activation of p53 and/or Rb by NPM-ALK triggers a potent proliferative block with features reminiscent of senescence. While loss of p53 alone is sufficient to circumvent NPM-ALK-induced senescence and permit cellular transformation, sole loss of Rb permits continued proliferation but not transformation due to p53-imposed restraints. Furthermore, NPM-ALK attenuates p53 activity in an Rb and MDM2 dependent manner but this activity is not sufficient to bypass senescence. These data indicate that senescence may constitute an effective barrier to ALK-induced malignancies that ultimately must be overcome for tumor development.
doi:10.1371/journal.pone.0017854
PMCID: PMC3056788  PMID: 21423761
4.  Aberrant expression of IL-22 receptor 1 (IL-22R1) and autocrine IL-22 stimulation contribute to tumorigenicity in ALK-positive anaplastic large cell lymphoma 
One of the characteristic features of anaplastic lymphoma kinase (ALK)-positive, anaplastic large cell lymphoma (ALK+ALCL) is the constitutive activation of STAT3, a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimulatory loop involving interleukin-22 (IL-22) that contributes to STAT3 activation and tumorigenicity of ALK+ALCL. The IL-22 receptor, a heterodimer composed of IL-22R1 and IL-10R2, was expressed in all ALK+ALCL cell lines and tumors examined. The expression of IL-22R1 in ALK+ALCL is aberrant, since this protein is absent in benign lymphocytes. While ALK+ALCL cells produce endogenous IL-22, addition of recombinant IL-22 to ALK+ALCL cell lines significantly increased STAT3 activation, cell proliferation and colony formation in soft agar. Opposite biological effects were observed in cells treated with recombinant IL-22BP (a naturally-occurring IL-22 decoy) or IL-22 neutralizing antibody. NPM-ALK, the characteristic fusion gene oncoprotein expressed in ALK+ALCL, directly contributes to the aberrant expression of IL-22R1, since transfection of NPM-ALK in Jurkat cells induced IL-22R1 expression and IL-22-mediated STAT3 activation. To conclude, for the first time, we demonstrate the importance of the IL-22 autocrine pathway in a lymphoid malignancy, and reveal yet another novel function of NPM-ALK.
doi:10.1038/leu.2008.129
PMCID: PMC3429118  PMID: 18509351
anaplastic large cell lymphoma; IL-22; tumorigenicity; STAT3; NPM-ALK
5.  Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis 
Heterozygous expression of Nucleophosmin (NPM1) predisposes to hematological malignancies in the mouse and cooperates with Myc in lymphomagenesis. NPM1 is therefore regarded as a haploinsufficient tumor suppressor. Heterozygous loss of NPM1 occurs as a result of the t(2;5) which generates the oncogenic fusion tyrosine kinase, NPM-Anaplastic Lymphoma Kinase (ALK), a molecule underlying the pathogenesis of Anaplastic Large Cell Lymphoma (ALCL). Given the aforementioned role of NPM1 as a tumor suppressor we hypothesized that NPM1 heterozygosity would cooperate with NPM-ALK in lymphomagenesis. In the event, we observed no difference in tumor latency, incidence or phenotype in NPM-ALK-transgenic mice heterozygous for NPM1 relative to transgenic mice expressing both NPM1 alleles. We propose that whilst the t(2;5) simultaneously reduces NPM1 allelic dosage and creates the NPM-ALK fusion protein, the two events do not cooperate in the pathogenesis of ALCL in our mouse model. These data indicate that a tumor-suppressive role for NPM1 may be dependant on cellular and/or genetic context.
ALCL = Anaplastic Large Cell Lymphoma, ALK = Anaplastic Lymphoma Kinase, NPM1 = Nucleophosmin, MPD = myeloproliferative disorder, ML = myeloid leukemia
doi:10.1038/labinvest.2011.96
PMCID: PMC3166849  PMID: 21709672
ALCL; lymphoma; mouse model; NPM-ALK; NPM1
6.  The heat shock protein-90 co-chaperone, Cyclophilin 40, promotes ALK-positive, anaplastic large cell lymphoma viability and its expression is regulated by the NPM-ALK oncoprotein 
BMC Cancer  2012;12:229.
Background
Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is a T cell lymphoma defined by the presence of chromosomal translocations involving the ALK tyrosine kinase gene. These translocations generate fusion proteins (e.g. NPM-ALK) with constitutive tyrosine kinase activity, which activate numerous signalling pathways important for ALK+ ALCL pathogenesis. The molecular chaperone heat shock protein-90 (Hsp90) plays a critical role in allowing NPM-ALK and other signalling proteins to function in this lymphoma. Co-chaperone proteins are important for helping Hsp90 fold proteins and for directing Hsp90 to specific clients; however the importance of co-chaperone proteins in ALK+ ALCL has not been investigated. Our preliminary findings suggested that expression of the immunophilin co-chaperone, Cyclophilin 40 (Cyp40), is up-regulated in ALK+ ALCL by JunB, a transcription factor activated by NPM-ALK signalling. In this study we examined the regulation of the immunophilin family of co-chaperones by NPM-ALK and JunB, and investigated whether the immunophilin co-chaperones promote the viability of ALK+ ALCL cell lines.
Methods
NPM-ALK and JunB were knocked-down in ALK+ ALCL cell lines with siRNA, and the effect on the expression of the three immunophilin co-chaperones: Cyp40, FK506-binding protein (FKBP) 51, and FKBP52 examined. Furthermore, the effect of knock-down of the immunophilin co-chaperones, either individually or in combination, on the viability of ALK+ ALCL cell lines and NPM-ALK levels and activity was also examined.
Results
We found that NPM-ALK promoted the transcription of Cyp40 and FKBP52, but only Cyp40 transcription was promoted by JunB. We also observed reduced viability of ALK+ ALCL cell lines treated with Cyp40 siRNA, but not with siRNAs directed against FKBP52 or FKBP51. Finally, we demonstrate that the decrease in the viability of ALK+ ALCL cell lines treated with Cyp40 siRNA does not appear to be due to a decrease in NPM-ALK levels or the ability of this oncoprotein to signal.
Conclusions
This is the first study demonstrating that the expression of immunophilin family co-chaperones is promoted by an oncogenic tyrosine kinase. Moreover, this is the first report establishing an important role for Cyp40 in lymphoma.
doi:10.1186/1471-2407-12-229
PMCID: PMC3407532  PMID: 22681779
7.  The Anaplastic Lymphoma Kinase controls cell shape and growth of Anaplastic Large Cell Lymphoma through Cdc42 activation 
Cancer research  2008;68(21):8899-8907.
Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin Lymphoma (NHL) that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the Anaplastic Lymphoma Kinase (ALK) gene. Proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the Nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filaments assembly in a pattern similar to T-Cell Receptor (TCR) stimulated cells. NPM-ALK formed a complex with the Guanine Exchange Factor (GEF) VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity and, in turn, Cdc42 regulated the shape and the migration of ALCL cells. In vitro knock-down of VAV1 or Cdc42 by sh-RNA, as well as pharmacological inhibition of Cdc42 activity by secramine, resulted in a cell-cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cells growth through Cdc42.
doi:10.1158/0008-5472.CAN-08-2568
PMCID: PMC2596920  PMID: 18974134
Lymphoma; Anaplastic; ALK; Cdc42; VAV1
8.  Inhibition of Rac controls NPM–ALK-dependent lymphoma development and dissemination 
Blood Cancer Journal  2011;1(6):e21-.
Nucleophosmin-anaplastic lymphoma kinase (NPM–ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM–ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM–ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM–ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.
doi:10.1038/bcj.2011.19
PMCID: PMC3255265  PMID: 22829165
anaplastic lymphomas; NPM–ALK; dissemination; Rac1 GTPase
9.  Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients 
Background
Systemic anaplastic large cell lymphoma (S-ALCL) is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK) has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL.
Results
The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7) and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK+) and ALK negative (ALK-) was age, with a younger median age of 22 for ALK+ compared with 30 for ALK-. However, when pediatric patients (≤18) were excluded, there was no age difference between ALK+ and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51%) or those with extranodal disease (53 vs 59%). Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14 years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1) and B-cell lymphoma 2 protein (BCL-2) correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor.
Conclusions
Our results show that ALK expression alone is not sufficient to determine the outcome of ALCL and other prognostic factors must be considered. Clinical stage is an independent prognostic factor. Ki-67 expression is a promising prognostic factor.
doi:10.1186/1756-8722-5-38
PMCID: PMC3418559  PMID: 22769020
Systemic anaplastic large cell lymphoma; Prognosis; Anaplastic lymphoma kinase; Ki-67; BCL-2; WT1
10.  Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma 
BMC Cancer  2013;13:471.
Backgroud
Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL.
Methods
A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells.
Results
ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK.
Conclusions
Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.
doi:10.1186/1471-2407-13-471
PMCID: PMC3852000  PMID: 24112608
Anaplastic large cell lymphoma (ALCL); Anaplastic lymphoma kinase (ALK); AKT; mTOR; 4E-BP1; p-70S6K1; Prognosis
11.  ANALYSIS OF HUMAN T-CELL LYMPHOTROPIC VIRUS IN CD25-POSITIVE-ANAPLASTIC LARGE CELL LYMPHOMAS IN CHILDREN 
T-cell lymphomas are rare in children. Anaplastic large cell lymphoma (ALCL) is the most common pediatric mature T-cell lymphoma, accounting for about 10-20% of all pediatric non-Hodgkin lymphoma. ALCL is now recognized as two distinct diseases, i.e., ALCL-ALK-positive (ALCL- ALK+) and ALCL-ALK-negative (ALCL- ALK-); ALK-positive ALCL presents at a younger age and has a better prognosis. The human T-cell lymphotropic virus (HTLV-1) is a retrovirus that mainly infects helper T lymphocytes and is linked to the development of adult T-cell leukemia/lymphoma (ATLL). The other type of lymphoma related to this virus family is hairy cell leukemia (HCL). Both of these neoplasms frequently express CD25 (alpha chain-IL-2 receptor). Recently, it was demonstrated that CD25 is significantly expressed in childhood ALCL (75%). In Brazil, HTLV-1 infection is considered endemic, and vertical transmission is responsible for spread to children, and it is important to point out that 90% or more of the HTLV-1 carriers remain asymptomatic. Some cases of HTLV-1-related lymphomas in adults are described as having characteristics of ALCL, but are considered to be CD30-positive subtypes of ATLL based on the virologic findings. No similar cases have been described in children, therefore we analyzed 33 cases of pediatric ALCL, both CD25-positive and CD25-negative, looking for the presence of proviral HTLV-1 DNA, by PCR. All cases corresponded to the common histological type of ALCL and were CD30-positive in virtually all neoplastic cells. ALK expression was observed in all but two cases (93.9%), while CD25 was positive in 27 cases (82%), including one of the ALCL-ALK-. There was a strong positive correlation between ALK and CD25 expression. None of the cases showed proviral HTLV-1-DNA presence. Our study concludes that ALCL in children has no relationship with HTLV-1 and the high frequency of CD25 expression must be explained by a different mechanism than that described in ATLL.
doi:10.1309/AJCP6Q7QMUVGMVMF
PMCID: PMC2771325  PMID: 19864230
malignant lymphoma; T-cell lymphoma; anaplastic large cell lymphoma; HTLV-1; virus-related lymphomas; CD25; children
12.  Brain metastasis of ALK positive anaplastic large cell lymphoma after a long-term disease free survival in an old adult 
Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma composed of CD30-positive cells and now recognized as three different entities: primary cutaneous ALCL, primary systemic anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and primary ALK-negative (ALK-) ALCL. ALK+ ALCL is supposed to have a better prognosis than ALK- ALCL. It is rarely metastasized to other sites, especially to the central nervous system (CNS). Herein, we present a rare case of systemic ALK+ ALCL which metastasized to the brain after a long-term disease free survival in an adult. Neuroimaging revealed a well-enhanced mass in the left frontal lobe. And it was completely resected. The results of the pathological and immunohistochemical studies were consistent with the metastasized ALK+ ALCL. The clinical findings, pathologic characteristics and treatment are described.
PMCID: PMC3971325  PMID: 24696735
ALCL; ALK-positive; CNS; metastasis
13.  Inhibition of N-linked glycosylation impairs ALK phosphorylation and disrupts pro-survival signaling in neuroblastoma cell lines 
BMC Cancer  2011;11:525.
Background
The Anaplastic Lymphoma Kinase (ALK) is an orphan receptor tyrosine kinase, which undergoes post-translational N-linked glycosylation. The catalytic domain of ALK was originally identified in the t(2;5) translocation that produces the unglycosylated oncogenic protein NPM-ALK, which occurs in Anaplastic Large Cell Lymphoma (ALCL). Recently, both germline and somatic activating missense mutations of ALK have been identified in neuroblastoma (NB), a pediatric cancer arising from neural crest cells. Moreover, we previously reported that ALK expression is significantly upregulated in advanced/metastatic NB. We hypothesized that ALK function may depend on N-linked glycosylation and that disruption of this post-translational modification would impair ALK activation, regardless the presence of either gene mutations or overexpression.
Methods
We employed tunicamycin to inhibit N-linked glycosylation. The following ALK-positive NB cell lines were used: SH-SY5Y and KELLY (ALK mutation F1174L), UKF-NB3 (ALK mutation R1275Q) and NB1 (ALK amplification). As a control, we used the NB cell lines LA1-5S and NB5 (no ALK expression), and the ALCL cell line SU-DHL1 (NPM-ALK).
Results
Tunicamycin treatment of ALK-positive NB cells resulted in a hypoglycosylated ALK band and in decreased amounts of mature full size receptor. Concomitantly, we observed a marked reduction of mature ALK phosphorylation. On the contrary, tunicamycin had no effects on NPM-ALK phosphorylation in SU-DHL1 cells. Moreover, phosphorylation levels of ALK downstream effectors (AKT, ERK1/2, STAT3) were clearly impaired only in ALK mutated/amplified NB cell lines, whereas no significant reduction was observed in both ALK-negative and NPM-ALK-positive cell lines. Furthermore, inhibition of N-linked glycosylation considerably impaired cell viability only of ALK mutated/amplified NB cells. Finally, the cleavage of the Poly-ADP-ribose-polymerase (PARP) suggested that apoptotic pathways may be involved in cell death.
Conclusions
In this study we showed that inhibition of N-linked glycosylation affects ALK phosphorylation and disrupts downstream pro-survival signaling, indicating that inhibition of this post-translational modification may be a promising therapeutic approach. However, as tunicamycin is not a likely candidate for clinical use other approaches to alter N-linked glycosylation need to be explored. Future studies will assess whether the efficacy in inhibiting ALK activity might be enhanced by the combination of ALK specific small molecule and N-linked glycosylation inhibitors.
doi:10.1186/1471-2407-11-525
PMCID: PMC3267831  PMID: 22192458
14.  ALK-immunoreactive neoplasms 
Context
Since the first discovery of anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by Morris et al in 1994, the number of ALK-positive neoplasms, either in the form of translocation or gain-of-function mutations, have been dramatically expanded from ALCL of T- and NK-cell origin, to diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor (IMT), neuroblastoma, non-small cell lung carcinoma (NSCLC), undifferentiated anaplastic thyroid carcinoma, and rare type of sarcomas.
Objective
This review covers the major aspects of ALK-immunoreactive neoplasms with emphasis on the pathogenesis of ALK-positive neoplasms. The new advances and rapid-evolving practices using ALK inhibitors for therapy are also discussed at the end of this review.
Data Sources
ALK(+) articles published in English literature are retrieved and critically reviewed.
Conclusion
ALK(+) neoplasia is a rapidly growing field and the list of ALK(+) neoplasms is being expanded continuously. Accurate and correct diagnosis of ALK(+) neoplasms is of paramount importance in guiding the appropriate treatment in the era of personalized medicine using specific ALK inhibitor.
PMCID: PMC3396068  PMID: 22808292
Anaplastic lymphoma kinase (ALK); anaplastic large cell lymphoma (ALCL); ALK-positive neoplasms
15.  Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma 
Blood  2004;105(2):827-829.
Anaplastic large cell lymphoma (ALCL) is a highly proliferative neoplasm that frequently carries the t(2;5)(p23;q35) and aberrantly expresses nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). Previously, NPM-ALK had been shown to activate the phosphatidylinositol 3 kinase (PI3K)/Akt pathway. As the cyclin-dependent kinase (CDK) inhibitor p27Kip1 (p27) is usually not expressed in ALCL, we hypothesized that activated Akt (pAkt) phosphorylates p27 resulting in increased p27 proteolysis and cell cycle progression. Here we demonstrate that inhibition of pAkt activity in ALCL decreases p27 phosphorylation and degradation, resulting in increased p27 levels and cell cycle arrest. Using immunohistochemistry, pAkt was detected in 24 (57%) of 42 ALCL tumors, including 8 (44%) of 18 ALK-positive tumors and 16 (67%) of 24 ALK-negative tumors, and was inversely correlated with p27 levels. The mean percentage of p27-positive tumor cells was 5% in the pAkt-positive group compared with 26% in the pAkt-negative group (P = .0076). These findings implicate that Akt activation promotes cell cycle progression through inactivation of p27 in ALCL.
doi:10.1182/blood-2004-06-2125
PMCID: PMC1382060  PMID: 15374880
16.  Discovery of a Potent Inhibitor of Anaplastic Lymphoma Kinase with in Vivo Antitumor Activity 
ACS Medicinal Chemistry Letters  2010;1(9):493-498.
A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.
doi:10.1021/ml100158s
PMCID: PMC4007912  PMID: 24900237
Anaplastic lymphoma kinase inhibitor; ALK; anaplastic large cell lymphoma; ALCL
17.  Pathobiology of Anaplastic Large Cell Lymphoma 
Advances in Hematology  2011;2010:345053.
The authors revise the concept of anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.
doi:10.1155/2010/345053
PMCID: PMC3038421  PMID: 21331150
18.  ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination 
Journal of Clinical Pathology  2000;53(6):445-450.
Aims—In anaplastic large cell lymphoma (ALCL), the site of origin has been described as an important prognostic factor. Recently, a fusion protein containing anaplastic lymphoma kinase (ALK) was described in systemic nodal ALCL, and shown to be associated with a good prognosis. The aims of this study were to investigate whether the presence of ALK protein differs between ALCL of different sites of origin; to determine whether ALK expression occurs before dissemination to other sites; and, finally, to investigate whether the site of origin remains a prognostic parameter in ALK negative ALCL.
Methods—ALK expression, as detected by immunohistochemistry using the monoclonal antibodies ALK1 and ALKc, was studied in 85 ALCLs from different sites of origin. In 22 patients, ALK expression was studied in multiple biopsies from different sites (including 13 skin, 16 lymph node, and nine other). Overall survival time was analysed using the Kaplan Meier method.
Results—ALK expression was found in 20 of 51 systemic ALCLs with (primary) nodal involvement. No ALK expression was found in 15 primary cutaneous, 14 gastrointestinal, and five nasal ALCLs. Multiple and subsequent biopsies of patients showed ALK expression to be identical to that seen in the primary diagnostic biopsy. Kaplan Meier survival curves showed that in ALK negative ALCLs originating from different sites, primary cutaneous cases are associated with an excellent overall survival, whereas the other cases show a comparable five years survival of less than 40%.
Conclusions—If present, ALK expression favours systemic ALCL with (primary) nodal involvement, and can be used in differentiating between extranodal involvement of systemic (nodal) ALCL and primary extranodal ALCL. ALK is expressed consistently in multiple biopsies of a given patient, indicating that the chromosomal abnormality leading to aberrant ALK expression occurs before dissemination to other sites. Finally, in ALK negative non-cutaneous ALCLs, different sites of origin show comparable poor survival.
Key Words: anaplastic large cell lymphoma • extranodal • anaplastic lymphoma kinase • survival
doi:10.1136/jcp.53.6.445
PMCID: PMC1731216  PMID: 10911802
19.  ALK-negative anaplastic large cell lymphoma primarily involving the bronchus: a case report and literature review 
Anaplastic large cell lymphoma (ALCL) is a mature T cell lymphoma with characteristic morphologic, immunophenotypic and cytogenetic features. Current WHO classification includes anaplastic lymphoma kinase (ALK)-positive and ALK-negative variants. ALCL rarely presents with obstructive symptoms of the main airway. In addition to reporting a HIV-associated bronchial ALK-negative ALCL in a 44 year-old female, our literature review identified eight cases of bronchial ALCL with several interesting clinicopathological features, including: 1) a female predominance (67%); 2) two thirds of patients younger than 18 years old; 3) uniformly presented with respiratory symptoms and progressed to respiratory failure; 4) the tumor involving the main airways; 5) often with localized disease at the initial presentation. This unusual presentation of ALCL may pose as a diagnostic pitfall and delay the treatment.
PMCID: PMC3885507  PMID: 24427373
Anaplastic large cell lymphoma; anaplastic lymphoma kinase; bronchus; respiratory failure; HIV
20.  High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma 
Journal of Clinical Pathology  2005;58(5):520-524.
Aim: To gain more insight into the genes involved in the aetiology and pathogenesis of anaplastic large cell lymphoma (ALCL).
Methods: Serial analysis of gene expression (SAGE) was undertaken on the CD4+ALK+ (anaplastic lymphoma kinase positive) ALCL derived cell line Karpas299 and as comparison on CD4+ T cells. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were performed on five ALCL derived cell lines and 32 tissue samples to confirm the SAGE data.
Results: High expression of Mcl-1 was seen in the Karpas299 cell line, whereas the two other antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-XL, were not detected in the SAGE library. Quantitative RT-PCR confirmed the high expression of Mcl-1 mRNA and low expression of Bcl-2 and Bcl-XL in Karpas299 and in four other ALCL cell lines. To expand on these initial observations, primary tissue samples were analysed for Mcl-1, Bcl-XL, and Bcl-2 by immunohistochemistry. All 23 ALK+ and nine ALK− ALCL cases were positive for Mcl-1. Bcl-2 and Bcl-XL were expressed infrequently in ALK+ ALCL cases, but were present in a higher proportion of ALK− ALCL cases.
Conclusion: The consistent high expression of Mcl-1 in ALK+ and ALK− ALCL suggests that Mcl-1 is the main antiapoptotic protein in this disease. The high frequency of Mcl-1, Bcl-2, and Bcl-XL positive ALCL cases in the ALK− group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL.
doi:10.1136/jcp.2004.022335
PMCID: PMC1770666  PMID: 15858125
anaplastic large cell lymphoma; ALK; Bcl-2; Bcl-X L; Mcl-1
21.  The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update 
Extensive research has been carried out in the past two decades to study the pathobiology of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which is an oncogenic fusion protein found exclusively in a specific type of T-cell lymphoid malignancy, namely ALK-positive anaplastic large cell lymphoma. Results from these studies have provided highly useful insights into the mechanisms by which a constitutively tyrosine kinase, such as NPM-ALK, promotes tumorigenesis. Several previous publications have comprehensively summarized the advances in this field. In this review, we provide readers with a brief update on specific areas of NPM-ALK pathobiology. In the first part, the NPM-ALK/signal transducer and activator of transcription 3 (STAT3) signaling axis is discussed, with an emphasis on the existence of multiple biochemical defects that have been shown to amplify the oncogenic effects of this signaling axis. Specifically, findings regarding JAK3, SHP1 and the stimulatory effects of several cytokines including interleukin (IL)-9, IL-21 and IL-22 are summarized. New concepts stemming from recent observations regarding the functional interactions among the NPM-ALK/STAT3 axis, β catenin and glycogen synthase kinase 3β will be postulated. Lastly, new mechanisms by which the NPM-ALK/STAT3 axis promotes tumorigenesis, such as its modulations of Twist1, hypoxia-induced factor 1α, CD274, will be described. In the second part, we summarize recent data generated by mass spectrometry studies of NPM-ALK, and use MSH2 and heat shock proteins as examples to illustrate the use of mass spectrometry data in stimulating new research in this field. In the third part, the evolving field of microRNA in the context of NPM-ALK biology is discussed.
doi:10.1177/2040620712471553
PMCID: PMC3629756  PMID: 23610619
NPM-ALK; STAT3; anaplastic large cell lymphoma; oncogenic tyrosine kinase; signalling
22.  Clinical presentation of anaplastic large-cell lymphoma in the central nervous system 
Molecular and Clinical Oncology  2013;1(4):655-660.
The majority of primary central nervous system (CNS) lymphomas are diffuse large B-cell lymphomas (DLBCLs) and anaplastic large-cell lymphoma (ALCL) is a type of T-cell tumor that is rare in the CNS. The aim of this study was to elucidate the clinical presentation and standard therapy of ALCLs by investigating reported cases. Additionally, a case of anaplastic lymphoma kinase (ALK)-positive ALCL in a 20-year-old man who exhibited no recurrence for >5 years following high-dose methotrexate (HD-MTX) treatment was described. Twenty-six immunocompetent patients with ALCL of the CNS that were previously reported and 1 case of ALCL of the CNS treated at our hospital were investigated. Overall survival (OS) was analyzed in relation to survival factors such as age, ALK status and the treatment regimen. The male:female ratio of the patients was 19:8. Of the 27 patients, 13 (48.1%) were ALK-positive, 9 (33.3%) were ALK-negative and the ALK status was not determined in the remaining 5 patients (18.5%). ALK-positive ALCL occurred at a younger age (median age, 17 years) and exhibited a favorable course (5-year OS, 75.0%), whereas ALK-negative ALCL presented at an older age (median age, 65 years) and resulted in fatal outcomes (5-year OS, <12.5%). Similar to the findings for systemic ALCL, ALK positivity, age <40 years and chemotherapy are associated with long-term survival for ALCL of the CNS. Chemoradiotherapy including methotrexate is recommended for ALCL and the possibility of treatment with chemotherapy alone for ALK-positive ALCL is currently under consideration.
doi:10.3892/mco.2013.110
PMCID: PMC3915681  PMID: 24649224
primary central nervous system lymphoma; anaplastic large-cell lymphoma; anaplastic lymphoma kinase; T-cell lymphoma
23.  Molecular and Functional Characterizations of the Association and Interactions between Nucleophosmin-Anaplastic Lymphoma Kinase and Type I Insulin-Like Growth Factor Receptor1,2 
Neoplasia (New York, N.Y.)  2013;15(6):669-683.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects. We have also found that a single mutation of the Tyr644 or Tyr664 residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr644 and Tyr664 abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPM-ALKY644,664F completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr644 and Tyr664 diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr644 and Tyr664 appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.
PMCID: PMC3664999  PMID: 23730215
24.  Anaplastic lymphoma kinase: signalling in development and disease 
Biochemical Journal  2009;420(Pt 3):345-361.
RTKs (receptor tyrosine kinases) play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification or rearrangement of the corresponding genes. The ALK (anaplastic lymphoma kinase) RTK was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to NPM (nucleophosmin) in the t(2;5) chromosomal rearrangement associated with ALCL (anaplastic large cell lymphoma). To date, many chromosomal rearrangements leading to enhanced ALK activity have been described and are implicated in a number of cancer types. Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)–ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer. In the present review we address the role of ALK in development and disease and discuss implications for the future.
doi:10.1042/BJ20090387
PMCID: PMC2708929  PMID: 19459784
anaplastic lymphoma kinase (ALK); anaplastic large cell lymphoma (ALCL); extracellular-signal-regulated kinase (ERK); inflammatory myofibroblastic tumour (IMT); midkine; neuroblastoma; non-small cell lung cancer (NSLCL); pleiotrophin; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; ALO17, ALK lymphoma oligomerization partner on chromosome 17; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase; BCR-Abl, breakpoint cluster region-Abl; CARS, cysteinyl-tRNA synthetase; Cdc42, cell division cycle 42; C/EBPβ, CCAAT/enhancer-binding protein β; CLTC, clathrin heavy chain; CML, chronic myeloid leukaemia; CNS, central nervous system; dALK, Drosophila ALK; DLBCL, diffuse large B-cell lymphoma; Dpp, decapentaplegic; DRG, dorsal root ganglia; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein like 4; ERK, extracellular-signal-regulated kinase; FOXO3a, forkhead box O 3a; FRS2, fibroblast growth factor receptor substrate 2; GIST, gastrointestinal stromal tumour; Grb2, growthfactor-receptor-bound protein 2; HEK, human embryonic kidney; Hen-1, hesitation-1; IL-3, interleukin-3; IMT, inflammatory myofibroblastic tumour; IR, insulin receptor; IRS-1, IR substrate-1; JAK, Janus kinase; Jeb, jelly belly; JNK, c-Jun N-terminal kinase; LDLa, low-density lipoprotein class A; LTK, leucocyte tyrosine kinase; MAM, meprin, A5 protein and receptor protein tyrosine phosphatase mu; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MK, midkine; MSN, moesin; mTOR, mammalian target of rapamycin; MUC-1, mucin-1; MYH9, non-muscle myosin heavy chain; NF-κB, nuclear factor κB; NIPA, nuclear interacting partner of ALK; NPM, nucleophosmin; NSCLC, non-small cell lung cancer; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PLCγ, phospholipase Cγ; PTN, pleiotrophin; RANBP2, Ran-binding protein 2; RPTP, receptor protein tyrosine phosphatase; RTK, receptor tyrosine kinase; SCC, squamous cell carcinoma; SCD-2, suppressor of constitutive dauer 2; SEC31L1, SEC31 homologue A; SH2, Src homology 2; Shc, Src homology and collagen homology; SHH, sonic hedghog; Shp1, SH2 domain-containing phosphatase 1; STAT, signal transducer and activator of transcription; TFG, TRK-fused gene; TGFβ, transforming growth factor β; TPM, tropomyosin; UCN-01, unco-ordinated 1
25.  A Novel, Highly Sensitive Antibody Allows for the Routine Detection of ALK-rearranged Lung Adenocarcinomas by Standard Immunohistochemistry 
Purpose
Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK-rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in-situ hybridization (FISH) or immunohistochemical (IHC) assays. In the present study we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas (ALCL).
Experimental Design
We analyzed 174 tumors with one standard, and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists.
Results
ALK protein is invariably and exclusively expressed in ALK-rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK-rearranged tumor, anaplastic large cell lymphoma, and as a result, often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens with excellent interobserver agreement between pathologists (kappa statistic, 0.94).
Conclusions
Low levels of ALK protein expression is a characteristic feature of ALK-rearranged lung adenocarcinomas. However a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for FISH analysis for the majority of cases and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.
doi:10.1158/1078-0432.CCR-09-2845
PMCID: PMC2831135  PMID: 20179225
Lung adenocarcinoma; ALK; immunohistochemistry

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